Ultrastructural studies conducted during the presently funded period have provided anatomical substrates that monoamines are major modulators of septohippocampal neurons. They also suggest that the transmitter components (acetylcholine and gamma-aminobutyric acid (GABA)] of the septo-hippocampal pathway, via their divergent connectivity with interneurons containing GABA or neuropeptide Y (NPY) in the hippocampal formation (HF), play differing roles in hippocampal function. In the continuing grant proposal, the studies will more directly test in rat (and where relevant, monkey): (a) the receptor mediated mechanisms for monoamine (mostly noradrenaline; NA) actions on septohippocampal neurons; and (b) specificity of the expression of low affinity nerve growth factor receptors (p75NGF-R) for the transmitter components of septohippocampal neurons. The proposed studies will employ: (1) quantitative light microscopic immunocytochemical techniques; and (2) electron microscopic dual labeling techniques performed on single brain sections for localizing either two antigens or a single antigen in combination with tract-tracers. The goal of Study I is to determine if the diverse cellular relations between NA terminals and septohippocampal neurons in both the septal complex and HF is indicative of the intra- or extra- cellular localization of alpha-2 and beta-adrenergic receptors. Study II will test the premise that p75NGF-R are localized to specific pre- and postsynaptic regions within cholinergic septohippocampal neurons compared to non-cholinergic (e.g., GABA) septohippocampal neurons. Also, we will test the postulation that p75NGF-R containing terminals in the HF have differing ultrastructural relations with GABAergic neurons compared to NPY neurons. Study III will test the hypothesis that removal of cells that express p75NGF-R results in a selective destruction of cholinergic septohippocampal neurons and a change in the cellular relations of the remaining GABAergic septohippocampal neurons in both the septal complex and HF. We will also analyze whether the number, morphology or cellular relations of monoaminergic terminals in both regions and hippocampal NPY neurons change following removal of cells that express p75NGF-R. Study IV will compare the cellular relations of septohippocampal (primarily cholinergic) neurons with adrenergic receptors in the septal complex and GABAergic and NPY neurons in the HF of the monkey to those in the rat. These diverse, but highly complimentary studies, will provide essential basic science information on the receptor mediated actions of NA on septohippocampal neurons and the specificity of p75NGF-R for the transmitter components of these neurons. The studies will be carried out in adult male rats and monkeys, but will yield information that is directly applicable for devising improved therapeutic measures to manipulate transmitter systems disrupted by disorders such as Alzheimer's disease and epilepsy in humans.